This is an application for a K23 award for James Yi, MD, PhD, a child and adolescent psychiatrist with molecular biology background who is establishing himself as a young investigator in schizophrenia prodrome research. He is focusing on the role of immune dysfunction in psychosis risk. This Career Development Award will provide him with the necessary support to acquire expertise in immunology, enabling him to develop an independent research career, investigating early immune mechanisms associated with schizophrenia. He has proposed a coordinated training plan of research, mentorship and coursework. Along with his primary mentor, Dr. Raquel Gur, the Director of Neuropsychiatry program and Schizophrenia Center at University of Pennsylvania and co-mentor, Dr. Steve Douglas, the Director of Immunogenetics Laboratory at CHOP, he has assembled an Advisory Committee comprising experts in developmental psychopathology, neurocognition, advanced biostatics and research career development. Schizophrenia prodrome is a well-recognized window of opportunity for early intervention treatments and more studies have increasingly focused on identifying risk factors predictive of illness progression that could facilitate early interventions. Several convergent lines of evidence implicate the immune system in the pathophysiology of schizophrenia and may provide novel therapeutic targets. Notably, elevated levels of pro-inflammatory cytokines and increased total number of monocytes have been observed in patients with schizophrenia, implicating that inflammatory processes may contribute to the illness. However, because existing studies have been largely in adult patients, the role of immune system dysfunction during the prodrome is unclear. Capitalizing on a unique cohort of youths with clinical high-risk for psychosis established through the Philadelphia Neurodevelopmental Cohort, we propose to longitudinally examine both pro- and anti-inflammatory cytokines and monocyte subpopulations, along with a comprehensive assessment for subthreshold psychotic features and neurocognitive performances implicated in schizophrenia. By examining the trajectory of immune markers in relation to psychotic features, we believe the proposed study will clarify the nature of immune dysfunction and utility of immune markers in predicting the disease progression. Furthermore, this research will provide the basis for examining immune markers across multiple units of analysis such as genomic and neuroimaging data to be examined in future efforts.